Publications

Discoidin domain receptor 2 (DDR2) is an unusual receptor tyrosine kinase in that its ligand is fibrillar collagen rather than a growth factor-like peptide. We examined signal transduction pathways of DDR2. Here we show that DDR2 is also unusual in that it requires Src activity to be maximally tyrosine-phosphorylated, and that Src activity also promotes association of DDR2 with Shc. The interaction with Shc involves a portion of Shc not previously implicated in interaction with receptor tyrosine kinases. These results identify Src kinase and the adaptor protein Shc as key signaling intermediates in DDR2 signal transduction. Furthermore, Src is required for DDR2-mediated transactivation of the matrix metalloproteinase-2 promoter. The data support a model in which Src and the DDR2 receptor cooperate in a regulated fashion to direct the phosphorylation of both the receptor and its targets.

Abstract Advances in our understanding of the mechanisms involved in immune activation and immune tolerance have laid the foundation for the development of new strategies for treating autoimmune diseases. In particular, the dissection of the two-signal process of T-cell activation has identified distinct targets that may provide a means of blocking pathological autoimmune responses without causing sustained blockade of protective immune responses. These strategies have shown great promise in animal models for autoimmune diseases, and they are currently the focus of clinical investigation in several autoimmune diseases of humans.

BACKGROUND

Indirect evidence and modeling analyses suggest that colonoscopy may be the most cost-effective way to screen the average-risk population for colorectal neoplasia. However, the success and safety of primary colonoscopic screening has not been prospectively evaluated in a multicenter trial.

METHODS

Asymptomatic subjects age 50 to 75 years who had not undergone examination of the colon within 10 years were recruited from the general medicine clinics of 13 Department of Veterans Affairs Medical Centers. Eligible patients underwent colonoscopy by study coinvestigators, at which time all polyps were measured, photographed, and removed. Patients were contacted at 24 hours and 1 week to track procedure-related complications.

RESULTS

Primary screening colonoscopy was performed in a cohort of 3196 asymptomatic subjects. A "good" preparation was reported in 81% of patients, and colonoscopy to the cecum was successful in 97.2% of cases. Mean insertion time to the cecum and total procedure times were 10.5 (8.7) and 30.6 (19.1) minutes, respectively. No preprocedural patient characteristics were identified that were predictive of an incomplete procedure. At least one polyp was resected in 1672 patients. There was no perforation and no death attributed to colonoscopy. Major morbidity considered to be definitely related to colonoscopy occurred in 9 of 3196 procedures (0.3%): lower GI bleeding requiring intervention (6), myocardial infarction and/or cerebrovascular accident (2), and thrombophlebitis (1). In subjects undergoing only diagnostic procedures, the major complication rate was 0.1%.

CONCLUSIONS

Screening colonoscopy can be performed in multiple centers with a high degree of success and safety in large numbers of asymptomatic, average-risk men.